Suicidality and Antidepressant Drugs
`Antidepressants increased the risk compared to placebo of suicidal thinking and behavior
`(suicidality) in children, adolescents, and young adults in short-term studies of major
`depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use
`of nefazodone hydrochloride tablets or any other antidepressant in a child, adolescent, or
`young adult must balance this risk with the clinical need. Short-term studies did not show an
`increase in the risk of suicidality with antidepressants compared to placebo in adults beyond
`age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged
`65 and older. Depression and certain other psychiatric disorders are themselves associated
`with increases in the risk of suicide. Patients of all ages who are started on antidepressant
`therapy should be monitored appropriately and observed closely for clinical worsening,
`suicidality, or unusual changes in behavior. Families and caregivers should be advised of the
`need for close observation and communication with the prescriber. Nefazodone hydrochloride
`tablets are not approved for use in pediatric patients (see WARNINGS, Clinical Worsening and
`Suicide Risk; PRECAUTIONS, Information for Patients; and PRECAUTIONS, Pediatric Use).
`
`Before prescribing nefazodone hydrochloride tablets, the physician should be thoroughly familiar
`with the details of this prescribing information.
`
`Warning
`Cases of life-threatening hepatic failure have been reported in patients treated with nefazodone
`hydrochloride tablets. The reported rate in the United States is about 1 case of liver
`failure resulting in death or transplant per 250,000 to 300,000 patient-years of nefazodone
`hydrochloride treatment. The total patient-years is a summation of each patient’s duration of
`exposure expressed in years. For example, 1 patient-year is equal to 2 patients each treated for
`6 months, 3 patients each treated for 4 months, etc. (see WARNINGS).
`Ordinarily, treatment with nefazodone hydrochloride tablets should not be initiated in
`individuals with active liver disease or with elevated baseline serum transaminases. There
`is no evidence that pre-existing liver disease increases the likelihood of developing liver
`failure, however, baseline abnormalities can complicate patient monitoring.
`Patients should be advised to be alert for signs and symptoms of liver dysfunction
`(jaundice, anorexia, gastrointestinal complaints, malaise, etc.) and to report them to their
`doctor immediately if they occur.
`Nefazodone hydrochloride tablets should be discontinued if clinical signs or symptoms suggest
`liver failure (see PRECAUTIONS, Information for Patients). Patients who develop evidence of
`hepatocellular injury such as increased serum AST or serum ALT levels ≥ 3 times the upper limit
`of NORMAL, while on nefazodone hydrochloride tablets should be withdrawn from the drug. These
`patients should be presumed to be at increased risk for liver injury if nefazodone hydrochloride is
`reintroduced. Accordingly, such patients should not be considered for re-treatment.
`
`DESCRIPTION
`Nefazodone hydrochloride tablets USP are an antidepressant for oral administration with a
`chemical structure unrelated to selective serotonin reuptake inhibitors, tricyclics, tetracyclics, or
`monoamine oxidase inhibitors (MAOI).
`Nefazodone hydrochloride is a synthetically derived phenylpiperazine antidepressant. The
`chemical name for nefazodone hydrochloride is 2-[3-[4-(3-chlorophenyl)-1-piperazinyl]
`propyl]-5-ethyl-2,4-dihydro-4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-one monohydrochloride. The
`structural formula is:
`
`C2H5
`
`N
`
`N
`
`N
`
`O
`
`OCH2CH2
`
`CH2CH2CH2
`
`N
`
`N
`
`• HCI
`
`CI
`
`C25H32CIN5O2•HCl M.W. 506.5
`Nefazodone hydrochloride is a nonhygroscopic, white crystalline solid. It is freely soluble in
`chloroform, soluble in propylene glycol, and slightly soluble in polyethylene glycol and water.
`Nefazodone hydrochloride tablets USP are supplied as capsule-shaped tablets containing
`50 mg, 100 mg, 150 mg, 200 mg, or 250 mg of nefazodone hydrochloride and the following
`inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose,
`sodium starch glycolate and povidone. Additionally, the 50 mg tablets include ferric oxide
`red as a colorant, the 150 mg tablets include ferric oxide red and yellow as colorants, and the
`200 mg tablets include ferric oxide yellow as a colorant.
`CLINICAL PHARMACOLOGY
`Pharmacodynamics
`The mechanism of action of nefazodone, as with other antidepressants, is unknown.
`Preclinical studies have shown that nefazodone inhibits neuronal uptake of serotonin and
`norepinephrine.
`Nefazodone occupies central 5-HT2 receptors at nanomolar concentrations, and acts as an
`antagonist at this receptor. Nefazodone was shown to antagonize alpha1-adrenergic receptors,
`a property which may be associated with postural hypotension. In vitro binding studies
`showed that nefazodone had no significant affinity for the following receptors: alpha2 and beta
`adrenergic, 5-HT1A, cholinergic, dopaminergic, or benzodiazepine.
`Pharmacokinetics
`Nefazodone is rapidly and completely absorbed but is subject to extensive metabolism, so that
`its absolute bioavailability is low, about 20%, and variable. Peak plasma concentrations occur at
`about one hour and the half-life of nefazodone is 2 to 4 hours.
`Both nefazodone and its pharmacologically similar metabolite, hydroxynefazodone, exhibit
`nonlinear kinetics for both dose and time, with AUC and Cmax increasing more than proportionally
`with dose increases and more than expected upon multiple dosing over time, compared to
`single dosing. For example, in a multiple-dose study involving BID dosing with 50, 100, and
`200 mg, the AUC for nefazodone and hydroxynefazodone increased by about 4 fold with an
`increase in dose from 200 to 400 mg per day; Cmax increased by about 3 fold with the same
`dose increase. In a multiple-dose study involving BID dosing with 25, 50, 100, and 150 mg, the
`accumulation ratios for nefazodone and hydroxynefazodone AUC, after 5 days of BID dosing
`relative to the first dose, ranged from approximately 3 to 4 at the lower doses (50 to 100 mg/day)
`and from 5 to 7 at the higher doses (200 to 300 mg/day); there were also approximately 2 to
`4 fold increases in Cmax after 5 days of BID dosing relative to the first dose, suggesting extensive
`and greater than predicted accumulation of nefazodone and its hydroxy metabolite with multiple
`dosing. Steady-state plasma nefazodone and metabolite concentrations are attained within 4 to
`5 days of initiation of BID dosing or upon dose increase or decrease.
`Nefazodone is extensively metabolized after oral administration by n-dealkylation and aliphatic
`and aromatic hydroxylation, and less than 1% of administered nefazodone is excreted unchanged
`in urine. Attempts to characterize three metabolites identified in plasma, hydroxynefazodone
`(HO-NEF), meta-chlorophenylpiperazine (mCPP), and a triazole-dione metabolite, have been
`carried out. The AUC (expressed as a multiple of the AUC for nefazodone dosed at 100 mg BID)
`and elimination half-lives for these three metabolites were as follows:
`AUC Multiples and T1/2 for Three Metabolites of Nefazodone (100 mg BID)
`Metabolite
`AUC Multiple
`HO-NEF
`0.4
`mCPP
`0.07
`Triazole-dione
`4.0
`
`T1/2
`1.5 to 4 h
`4 to 8 h
`18 h
`
`NEFAZODONE
`HYDROCHLORIDE
`TABLETS USP
`(Patient Information Included)
`7178
`1024
`7113
`1025
`1026
`
` only
`Rev. M 5/2014
`322K063620514
`
`HO-NEF possesses a pharmacological profile qualitatively and quantitatively similar to that of
`nefazodone. mCPP has some similarities to nefazodone, but also has agonist activity at some
`serotonergic receptor subtypes. The pharmacological profile of the triazole-dione metabolite has
`not yet been well characterized. In addition to the above compounds, several other metabolites
`were present in plasma but have not been tested for pharmacological activity.
`After oral administration of radiolabeled nefazodone, the mean half-life of total label ranged
`between 11 and 24 hours. Approximately 55% of the administered radioactivity was detected in
`urine and about 20 to 30% in feces.
`Distribution
`Nefazodone is widely distributed in body tissues, including the central nervous system (CNS). In
`humans the volume of distribution of nefazodone ranges from 0.22 to 0.87 L/kg.
`Protein Binding
`At concentrations of 25 to 2500 ng/mL nefazodone is extensively (> 99%) bound to human
`plasma proteins in vitro. The administration of 200 mg BID of nefazodone for 1 week did not
`increase the fraction of unbound warfarin in subjects whose prothrombin times had been
`prolonged by warfarin therapy to 120 to 150% of the laboratory control (see PRECAUTIONS,
`Drug Interactions). While nefazodone did not alter the in vitro protein binding of chlorpromazine,
`desipramine, diazepam, diphenylhydantoin, lidocaine, prazosin, propranolol, or verapamil, it is
`unknown whether displacement of either nefazodone or these drugs occurs in vivo. There was
`a 5% decrease in the protein binding of haloperidol; this is probably of no clinical significance.
`Effect of Food
`Food delays the absorption of nefazodone and decreases the bioavailability of nefazodone by
`approximately 20%.
`Renal Disease
`In studies involving 29 renally impaired patients, renal impairment (creatinine clearances ranging from
`7 to 60 mL/min/1.73 m2) had no effect on steady-state nefazodone plasma concentrations.
`Liver Disease
`In a multiple-dose study of patients with liver cirrhosis, the AUC values for nefazodone and HO-NEF at
`steady state were approximately 25% greater than those observed in normal volunteers.
`Age/Gender Effects
`After single doses of 300 mg to younger (18 to 45 years) and older patients (> 65 years), Cmax
`and AUC for nefazodone and hydroxynefazodone were up to twice as high in the older patients.
`Reference ID: 3539843
`
`With multiple doses, however, differences were much smaller, 10 to 20%. A similar result was
`seen for gender, with a higher Cmax and AUC in women after single doses but no difference
`after multiple doses.
`Treatment with nefazodone should be initiated at half the usual dose in elderly patients, especially
`women (see DOSAGE AND ADMINISTRATION), but the therapeutic dose range is similar in
`younger and older patients.
`Clinical Efficacy Trial Results
`Studies in Outpatients With Depression
`During its premarketing development, the efficacy of nefazodone was evaluated at doses within
`the therapeutic range in five well-controlled, short-term (6 to 8 weeks) clinical investigations.
`These trials enrolled outpatients meeting DSM-III or DSM-IIIR criteria for major depression.
`Among these trials, two demonstrated the effectiveness of nefazodone, and two provided
`additional support for that conclusion.
`One trial was a 6 week dose-titration study comparing nefazodone in two dose ranges (up to
`300 mg/day and up to 600 mg/day [mean modal dose for this group was about 400 mg/day],
`on a BID schedule) and placebo. The second trial was an 8 week dose-titration study comparing
`nefazodone (up to 600 mg/day; mean modal dose was 375 mg/day), imipramine (up to
`300 mg/day), and placebo, all on a BID schedule. Both studies demonstrated nefazodone,
`at doses titrated between 300 mg to 600 mg/day (therapeutic dose range), to be superior to
`placebo on at least three of the following four measures: 17 Item Hamilton Depression Rating
`Scale or HDRS (total score), Hamilton Depressed Mood item, Clinical Global Impressions (CGI)
`Severity score, and CGI Improvement score. Significant differences were also found for certain
`factors of the HDRS (e.g., anxiety factor, sleep disturbance factor, and retardation factor). In the
`two supportive studies, nefazodone was titrated up to 500 or 600 mg/day (mean modal doses
`of 462 mg/day and 363 mg/day). In the fifth study, the differentiation in response rates between
`nefazodone and placebo was not statistically significant. Three additional trials were conducted
`using subtherapeutic doses of nefazodone.
`Overall, approximately two thirds of patients in these trials were women, and an analysis of the effects of
`gender on outcome did not suggest any differential responsiveness on the basis of sex. There were too
`few elderly patients in these trials to reveal possible age-related differences in response.
`Since its initial marketing as an antidepressant drug product, additional clinical investigations of
`nefazodone have been conducted. These studies explored nefazodone’s use under conditions not
`evaluated fully at the time initial marketing approval was granted.
`Studies in “Inpatients”
`Two studies were conducted to evaluate nefazodone’s effectiveness in hospitalized depressed
`patients. These were 6 week, dose-titration trials comparing nefazodone (up to 600 mg/day)
`and placebo, on a BID schedule. In one study, nefazodone was superior to placebo. In this
`study, the mean modal dose of nefazodone was 503 mg/day, and 85% of these inpatients
`were melancholic; at baseline, patients were distributed at the higher end of the 7 point CGI
`Severity scale, as follows: 4 = moderately ill (17%); 5 = markedly ill (48%); 6 = severely ill
`(32%). In the other study, the differentiation in response rates between nefazodone and placebo
`was not statistically significant. This result may be explained by the “high” rate of spontaneous
`improvement among the patients randomized to placebo.
`Studies of “Relapse Prevention in Patients Recently Recovered (Clinically) From Depression”
`Two studies were conducted to assess nefazodone’s capacity to maintain a clinical
`remission in acutely depressed patients who were judged to have responded adequately
`(HDRS total score ≤ 10) after a 16 week period of open treatment with nefazodone (titration up to
`600 mg/day). In one study, nefazodone was superior to placebo. In this study, patients (n = 131)
`were randomized to continuation on nefazodone or placebo for an additional 36 weeks (1 year
`total). This study demonstrated a significantly lower relapse rate (HDRS total score ≥ 18) for
`patients taking nefazodone compared to those on placebo. The second study was of appropriate
`design and power, but the sample of patients admitted for evaluation did not suffer relapses
`at a high enough incidence to provide a meaningful test of nefazodone’s efficacy for this use.
`Comparisons of Clinical Trial Results
`Highly variable results have been seen in the clinical development of all antidepressant drugs.
`Furthermore, in those circumstances when the drugs have not been studied in the same controlled
`clinical trial(s), comparisons among the findings of studies evaluating the effectiveness of different
`antidepressant drug products are inherently unreliable. Because conditions of testing (e.g., patient
`samples, investigators, doses of the treatments administered and compared, outcome measures, etc.)
`vary among trials, it is virtually impossible to distinguish a difference in drug effect from a difference
`due to one or more of the confounding factors just enumerated.
`INDICATIONS AND USAGE
`Nefazodone hydrochloride tablets are indicated for the treatment of depression. When deciding
`among the alternative treatments available for this condition, the prescriber should consider the
`risk of hepatic failure associated with nefazodone hydrochloride treatment (see WARNINGS). In
`many cases, this would lead to the conclusion that other drugs should be tried first.
`The efficacy of nefazodone in the treatment of depression was established in 6 to 8 week
`controlled trials of outpatients and in a 6 week controlled trial of depressed inpatients whose
`diagnoses corresponded most closely to the DSM-III or DSM-IIIR category of major depressive
`disorder (see CLINICAL PHARMACOLOGY).
`A major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood
`that usually interferes with daily functioning (nearly every day for at least 2 weeks). It must include
`either depressed mood or loss of interest or pleasure and at least five of the following nine symptoms:
`depressed mood, loss of interest in usual activities, significant change in weight and/or appetite,
`insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt
`or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation.
`The efficacy of nefazodone in reducing relapse in patients with major depression who
`were judged to have had a satisfactory clinical response to 16 weeks of open-label
`nefazodone treatment for an acute depressive episode has been demonstrated in a randomized
`placebo-controlled trial (see CLINICAL PHARMACOLOGY). Although remitted patients were
`followed for as long as 36 weeks in the study cited (i.e., 52 weeks total), the physician who elects
`to use nefazodone for extended periods should periodically reevaluate the long-term usefulness
`of the drug for the individual patient.
`CONTRAINDICATIONS
`Coadministration of terfenadine, astemizole, cisapride, pimozide, or carbamazepine with
`nefazodone hydrochloride is contraindicated (see WARNINGS and PRECAUTIONS).
`Nefazodone hydrochloride tablets are contraindicated in patients who were withdrawn
`from nefazodone because of evidence of liver injury (see BOXED WARNING). Nefazodone
`hydrochloride tablets are also contraindicated in patients who have demonstrated hypersensitivity
`to nefazodone hydrochloride, its inactive ingredients, or other phenylpiperazine antidepressants.
`The coadministration of triazolam and nefazodone causes a significant increase in the plasma
`level of triazolam (see WARNINGS and PRECAUTIONS), and a 75% reduction in the initial
`triazolam dosage is recommended if the two drugs are to be given together. Because not all
`commercially available dosage forms of triazolam permit a sufficient dosage reduction, the
`coadministration of triazolam and nefazodone should be avoided for most patients, including
`the elderly.
`WARNINGS
`Clinical Worsening and Suicide Risk
`Patients with major depressive disorder (MDD), both adult and pediatric, may experience
`worsening of their depression and/or the emergence of suicidal ideation and behavior
`(suicidality) or unusual changes in behavior, whether or not they are taking antidepressant
`medications, and this risk may persist until significant remission occurs. Suicide is a known
`risk of depression and certain other psychiatric disorders, and these disorders themselves
`are the strongest predictors of suicide. There has been a long-standing concern, however,
`that antidepressants may have a role in inducing worsening of depression and the emergence
`of suicidality in certain patients during the early phases of treatment. Pooled analyses of
`short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed
`that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children,
`adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other
`psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality
`with antidepressants compared to placebo in adults beyond age 24; there was a reduction with
`antidepressants compared to placebo in adults aged 65 and older.
`The pooled analyses of placebo-controlled trials in children and adolescents with MDD,
`obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-
`term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-
`controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-
`term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients.
`There was considerable variation in risk of suicidality among drugs, but a tendency toward an
`increase in the younger patients for almost all drugs studied. There were differences in absolute
`risk of suicidality across the different indications, with the highest incidence in MDD. The risk
`differences (drug vs placebo), however, were relatively stable within age strata and across
`indications. These risk differences (drug-placebo difference in the number of cases of suicidality
`per 1000 patients treated) are provided in Table 1.
`Table 1
`
`Age Range
`
`< 18
`18 to 24
`
`Drug-Placebo Difference in Number of Cases of
`Suicidality per 1000 Patients Treated
`Increases Compared to Placebo
`14 additional cases
`5 additional cases
`Decreases Compared to Placebo
`1 fewer case
`25 to 64
`6 fewer cases
`≥ 65
`No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the
`number was not sufficient to reach any conclusion about drug effect on suicide.
`It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several
`months. However, there is substantial evidence from placebo-controlled maintenance trials in
`adults with depression that the use of antidepressants can delay the recurrence of depression.
`
`All patients being treated with antidepressants for any indication should be monitored
`appropriately and observed closely for clinical worsening, suicidality, and unusual
`changes in behavior, especially during the initial few months of a course of drug therapy,
`or at times of dose changes, either increases or decreases.
`The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
`aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania,
`have been reported in adult and pediatric patients being treated with antidepressants for major
`depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.
`Although a causal link between the emergence of such symptoms and either the worsening of
`depression and/or the emergence of suicidal impulses has not been established, there is concern
`that such symptoms may represent precursors to emerging suicidality.
`Consideration should be given to changing the therapeutic regimen, including possibly
`discontinuing the medication, in patients whose depression is persistently worse, or who
`are experiencing emergent suicidality or symptoms that might be precursors to worsening
`depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not
`part of the patient’s presenting symptoms.
`Families and caregivers of patients being treated with antidepressants for major
`depressive disorder or other indications, both psychiatric and nonpsychiatric, should
`be alerted about the need to monitor patients for the emergence of agitation, irritability,
`unusual changes in behavior, and the other symptoms described above, as well as the
`emergence of suicidality, and to report such symptoms immediately to health care
`providers. Such monitoring should include daily observation by families and caregivers.
`Prescriptions for nefazodone hydrochloride tablets should be written for the smallest quantity
`of tablets consistent with good patient management, in order to reduce the risk of overdose.
`Screening Patients for Bipolar Disorder
`A major depressive episode may be the initial presentation of bipolar disorder. It is generally
`believed (though not established in controlled trials) that treating such an episode with an
`antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in
`patients at risk for bipolar disorder. Whether any of the symptoms described above represent
`such a conversion is unknown. However, prior to initiating treatment with an antidepressant,
`patients with depressive symptoms should be adequately screened to determine if they are at
`risk for bipolar disorder; such screening should include a detailed psychiatric history, including
`a family history of suicide, bipolar disorder, and depression. It should be noted that nefazodone
`hydrochloride tablets are not approved for use in treating bipolar depression.
`Angle-Closure Glaucoma
`The pupillary dilation that occurs following use of many antidepressant drugs including
`nefazodone hydrochloride tablets may trigger an angle closure attack in a patient with
`anatomically narrow angles who does not have a patent iridectomy.
`Hepatotoxicity
`(See BOXED WARNING.)
`Cases of life-threatening hepatic failure have been reported in patients treated with
`nefazodone hydrochloride tablets.
`The reported rate in the United States is about 1 case of liver failure resulting in death or
`transplant per 250,000 to 300,000 patient-years of nefazodone treatment. This represents
`a rate of about 3 to 4 times the estimated background rate of liver failure. This rate is an
`underestimate because of under reporting, and the true risk could be considerably greater
`than this. A large cohort study of antidepressant users found no cases of liver failure leading
`to death or transplant among nefazodone users in about 30,000 patient-years of exposure.
`The spontaneous report data and the cohort study results provide estimates of the upper and
`lower limits of the risk of liver failure in nefazodone-treated patients, but are not capable of
`providing a precise risk estimate.
`The time to liver injury for the reported liver failure cases resulting in death or transplant
`generally ranged from 2 weeks to 6 months on nefazodone therapy. Although some reports
`described dark urine and nonspecific prodromal symptoms (e.g., anorexia, malaise, and
`gastrointestinal symptoms), other reports did not describe the onset of clear prodromal
`symptoms prior to the onset of jaundice.
`The physician may consider the value of liver function testing. Periodic serum transaminase
`testing has not been proven to prevent serious injury but it is generally believed that early
`detection of drug-induced hepatic injury along with immediate withdrawal of the suspect drug
`enhances the likelihood for recovery.
`Patients should be advised to be alert for signs and symptoms of liver dysfunction (jaundice,
`anorexia, gastrointestinal complaints, malaise, etc.) and to report them to their doctor
`immediately if they occur. Ongoing clinical assessment of patients should govern physician
`interventions, including diagnostic evaluations and treatment.
`Nefazodone should be discontinued if clinical signs or symptoms suggest liver failure
`(see PRECAUTIONS, Information for Patients). Patients who develop evidence of
`hepatocellular injury such as increased serum AST or serum ALT levels ≥ 3 times the upper
`limit of NORMAL, while on nefazodone should be withdrawn from the drug. These patients
`should be presumed to be at increased risk for liver injury if nefazodone is reintroduced.
`Accordingly, such patients should not be considered for re-treatment.
`Potential for Interaction With Monoamine Oxidase Inhibitors
`In patients receiving antidepressants with pharmacological properties similar to nefazodone
`in combination with a monoamine oxidase inhibitor (MAOI), there have been reports of
`serious, sometimes fatal, reactions. For a selective serotonin reuptake inhibitor (SSRI), these
`reactions have included hyperthermia, rigidity, myoclonus, autonomic instability with possible
`rapid fluctuations of vital signs, and mental status changes that include extreme agitation
`progressing to delirium and coma. These reactions have also been reported in patients
`who have recently discontinued that drug and have been started on an MAOI. Some cases
`presented with features resembling neuroleptic malignant syndrome. Severe hyperthermia and
`seizures, sometimes fatal, have been reported in association with the combined use of tricyclic
`antidepressants and MAOIs. These reactions have also been reported in patients who have
`recently discontinued these drugs and have been started on an MAOI.
`Although the effects of combined use of nefazodone and MAOI have not been evaluated in
`humans or animals, because nefazodone is an inhibitor of both serotonin and norepinephrine
`reuptake, it is recommended that nefazodone not be used in combination with an MAOI, or
`within 14 days of discontinuing treatment with an MAOI. At least 1 week should be allowed
`after stopping nefazodone before starting an MAOI.
`Interaction With Triazolobenzodiazepines
`Interaction studies of nefazodone with two triazolobenzodiazepines, i.e., triazolam and
`alprazolam, metabolized by cytochrome P450 3A4, have revealed substantial and clinically
`important increases in plasma concentrations of these compounds when administered
`concomitantly with nefazodone.
`Triazolam
`When a single oral 0.25 mg dose of triazolam was coadministered with nefazodone (200 mg BID)
`at steady state, triazolam half-life and AUC increased 4 fold and peak concentrations increased
`1.7 fold. Nefazodone plasma concentrations were unaffected by triazolam. Coadministration
`of nefazodone potentiated the effects of triazolam on psychomotor performance tests. If
`triazolam is coadministered with nefazodone, a 75% reduction in the initial triazolam dosage
`is recommended. Because not all commercially available dosage forms of triazolam permit
`sufficient dosage reduction, coadministration of triazolam with nefazodone should be avoided for
`most patients, including the elderly. In the exceptional case where coadministration of triazolam
`with nefazodone may be considered appropriate, only the lowest possible dose of triazolam
`should be used (see CONTRAINDICATIONS and PRECAUTIONS).
`Alprazolam
`When alprazolam (1 mg BID) and nefazodone (200 mg BID) were coadministered, steady-state
`peak concentrations, AUC and half-life values for alprazolam increased by approximately
`2 fold. Nefazodone plasma concentrations were unaffected by alprazolam. If alprazolam
`is coadministered with nefazodone, a 50% reduction in the initial alprazolam dosage is
`recommended. No dosage adjustment is required for nefazodone.
`Potential Terfenadine, Astemizole, Cisapride, and Pimozide Interactions
`Terfenadine, astemizole, cisapride, and pimozide are all metabolized by the cytochrome P450 3A4
`(CYP3A4) isozyme, and it has been demonstrated that ketoconazole, erythromycin, and other
`inhibitors of CYP3A4 can block the metabolism of these drugs, which can result in increased
`plasma concentrations of parent drug. Increased plasma concentrations of terfenadine, astemizole,
`cisapride, and pimozide are associated with QT prolongation and with rare cases of serious
`cardiovascular adverse events, including death, due principally to ventricular tachycardia of
`the torsade de pointes type. Nefazodone has been shown in vitro to be an inhibitor of CYP3A4.
`Consequently, it is recommended that nefazodone not be used in combination with either
`terfenadine, astemizole, cisapride, or pimozide (see CONTRAINDICATIONS and PRECAUTIONS).
`Interaction With Carbamazepine
`The coadministration of carbamazepine 200 mg BID with nefazodone 200 mg BID, at
`steady state for both drugs, resulted in almost 95% reductions in AUCs for nefazodone and
`hydroxynefazodone, likely resulting in insufficient plasma nefazodone and hydroxynefazodone
`concentrations for achieving an antidepressant effect for nefazodone. Consequently, it
`is recommended that nefazodone not be used in combination with carbamazepine
`(see CONTRAINDICATIONS and PRECAUTIONS).
`PRECAUTIONS
`General
`Hepatotoxicity
`(See BOXED WARNING.)
`Postural Hypotension
`A pooled analysis of the vital signs monitored during placebo-controlled premarketing studies
`revealed that 5.1% of nefazodone patients compared to 2.5% of placebo patients (p ≤ 0.01) met
`criteria for a potentially important decrease in blood pressure at some time during treatment
`(systolic blood pressure ≤ 90 mmHg and a change from baseline of ≥ 20 mmHg). While
`there was no difference in the proportion of nefazodone and placebo patients having adverse
`events characterized as ‘syncope’ (nefazodone, 0.2%; placebo, 0.3%), the rates for adverse
`events characterized as ‘postural hypotension’ were as follows: nefazodone (2.8%), tricyclic
`antidepressants (10.9%), SSRI (1.1%), and placebo (0.8%). Thus, the prescriber should
`be aware that there is some risk of postural hypotension in association with nefazodone
`
`use. Nefazodone should be used with caution in patients with known cardiovascular or
`cerebrovascular disease that could be exacerbated by hypotension (history of myocardial
`infarction, angina, or ischemic stroke) and conditions that would predispose patients to
`hypotension (dehydration, hypovolemia, and treatment with antihypertensive medication).
`Activation of Mania/Hypomania
`During premarketing testing, hypoman